Loss of cell polarity regulators initiates pyroptosis in trophoblasts at the human maternal fetal interface
Patel, K.; Nguyen, J.; Shaha, S.; Zubkowski, A.; Riddell, M.
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The syncytiotrophoblast is the placental epithelial cell that forms the maternal surface of the human placenta, acting as a barrier and facilitating exchange between mother and fetus. Syncytiotrophoblast dysfunction is a feature of pregnancy pathologies, like preeclampsia. Dysfunctional syncytiotrophoblast display a loss of microvilli, a marker of aberrant apical-basal polarization, but little data exists about the regulation of syncytiotrophoblast polarity. Atypical protein kinase-c (aPKC) isoforms are conserved polarity regulators. Thus, we hypothesized that aPKC isoforms regulate syncytiotrophoblast polarity. Using human placental explant culture and primary trophoblasts, we found that loss of aPKC activity or expression induces syncytiotrophoblast gasdermin E dependent pyroptosis. We also establish that TNF- induces an isoform specific decrease in aPKC expression and gasdermin E dependent pyroptosis. Therefore, aPKCs are homeostatic regulators of syncytiotrophoblast function and a pathogenically relevant pro-inflammatory signal leads to a highly pro-inflammatory form of cell death at the maternal-fetal interface. Therefore, our results have important implications for the pathobiology of placental disorders.
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